Registration Dossier

LD50 Oral (rat): 3900mg/kg bw 
LD50 Dermal (rabbit): >5000mg/kg bw

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparing to guidelines/standards, basic data is given.

Qualifier:

according to guideline

Guideline:

other: no data (see comments)

Principles of method if other than guideline:

In this acute oral toxicity study, no details test guideline was presented. However, it is indicated that 10 animals (unspecified sex) per dose and 4 dose levels: 1730 mg/kg, 2470 mg/kg, 3510 mg/kg, and 5000 mg/kg. The results provided were: mortality, time of death of individual animals at different dose levels, signs of toxicity at each dose, and necropsy findings at each dose.

GLP compliance:

not specified

Test type:

other: no data

Species:

rat

Strain:

not specified

Sex:

not specified

Route of administration:

oral: unspecified

Doses:

1730 mg/kg, 2470 mg/kg, 3510 mg/kg, and 5000 mg/kg

No. of animals per sex per dose:

10 anmials per dose and unspecific sex

Control animals:

no

Details on study design:

- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs

Sex:

not specified

Dose descriptor:

LD50

Effect level:

3 900 mg/kg bw

95% CL:

>= 2 900 - <= 5 100

Mortality:

At 1730 mg/kg: 3/10 deaths (2 animals by day 1 and 1 anmial by day 4);
At 2470 mg/kg: 1/10 deaths (by day 1);
At 3510 mg/kg: 3/10 deaths (2 animals by day 1 and 1 animal by day 2).
At 5000 mg/kg: 9/10 deaths (6 animals by day 1, 2 animals by day 2 and 1 animal by day 3)

Clinical signs:

other: At 1730 mg/kg: diarrhea, lethargy; At 2470 mg/kg: lethargy, piloerection, diarrhea, ptosis; At 3510 mg/kg: lethargy, diarrhea, piloerection, comatose; At 5000 mg/kg: lethargy, piloerection, chromorhinorrhea

Table 1: Necropsy observation

Doses (mg/kg)	1730	2470	3510	5000
Normal	6		4
Cannibalized			1
Exudate, nose/mouth, red	1		1
Exudate, nose/mouth, yellow				5
Exudate, nose/mouth, clear			1
Exudate, nose/mouth, brown		1	1	6
Intestines, areas red	2		2	10
Intestines, areas yellow	1	1	2	8
Intestines, bloated			1	9
Stomach bloated				1
Liver dark	3		3	6
Liver mottled		6	1	1
Lungs, areas dark	3		2	2
Lungs, dark				6
Lungs, fourescent red				1
Kidney dark	4	4	2	8
Kidney mottled		4	1
Spleen dark			2	5
Spleen large			2	3
Spleen mottled	1
Bladder, blood contained		1		3

Interpretation of results:

other: Not classified according to CLP

Conclusions:

The acute median lethal oral doses (LD50) and their 95% confidence limits to rats of test substance was estimated to be:
LD 50: 3900 mg/kg bw (2900 - 5100 mg/kg bw; 95% C.I)

Executive summary:

In an acute oral toxicity study (1699 02/03), 40 rats (10 per group) were given single oral doses of Trigustral at 1730, 2470, 3510 and 5000 mg/kg bw and observed after dosing.

Oral LD 50: 3900 mg/kg bw (2900 - 5100 mg/kg bw; 95% C.I)

The following treatment-related effects were noted: clincal signs (lethargy, diarrhea with piloerection, chromorhinorrhea and ptosis noted with higher doses); mortality (at the lowest dosage, 3/10 animals dies; at the highest dosage, only one animal survived during 4 days observation period); necropsy observations (intestines, liver, lungs, kidney and spleen showed abnormalities that appeared dose related. The stomach and bladder showed sporadic abnormalities).

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

3 900 mg/kg bw

Quality of whole database:

The key study was the only study available and was assigned a Klimisch score of 2. The overall quality of the database is high.

Endpoint conclusion:

no study available

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparing to guidelines/standards, basic data is given.

Qualifier:

according to guideline

Guideline:

other: no data (see comments)

Principles of method if other than guideline:

In this acute dermal toxicity study, no details test guideline was presented. However, it is indicated that 10 animals (unspecified sex) were dosed in a limit test (5000 mg/kg). The results provided were: mortality, time of death of individual animals, signs of toxicity, necropsy findings.

GLP compliance:

not specified

Test type:

other: no data

Limit test:

yes

Species:

rabbit

Strain:

not specified

Sex:

not specified

Type of coverage:

not specified

Doses:

5000 mg/kg

No. of animals per sex per dose:

10 animals per dose and unspecific sex

Control animals:

no

Details on study design:

- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs

Sex:

not specified

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Mortality:

At 5000 mg/kg dose: 2/10 deaths (by day 2)

Clinical signs:

other: At 5000 mg/kg dose: anorexia, lessened mobility due to severe edema & eschar of exposure site, ptosis - Animal 1 - days 6 through day 14. Emaciated - Animal - day 14.

Table 1: Necropsy observations

Doses (mg/kg)	5000
Normal
Cannibalized
Exudate, nose/mouth, red
Exudate, nose/mouth, yellow	2
Exudate, nose/mouth, clear
Exudate, nose/mouth, brown
Intestines, areas red	3
Intestines, areas yellow	1
Intestines, bloated	1
Intestines, contained dark green substance	1
Stomach bloated
Liver dark	5
Liver mottled	1
Lungs, white nodules	2
Lungs, areas dark	2
Lungs, dark
Lungs, flourescent red
Kidney dark
Kidney mottled	2
Kidney pale	1
spleen dark
spleen large
spleen mottled
Skin, sloughing of exposure area	1
Skin edema	8
Skin redness	9
Skin, hard/thick	6
Bladder, blood contained

Interpretation of results:

other: Not classified according to CLP

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute dermal median lethal dose (LD50) of Trigustral in rabbits was found to be greater than 5000 mg/kg bw.

Executive summary:

In an acute dermal toxicity study (1699 02/03), 10 rabbits were given single dermal dose of Trigustral at 5000 mg/kg bw and observed up to 14 days after dosing.

Dermal LD 50: >5000 mg/kg bw

There were 2/10 deaths on day 1. Signs of toxicity noted in animal 1 from day 6 through day 14 were anorexia, lessened mobility due to severe edema & eschar of exposure site and ptosis; animal 1 was emaciated by day 14. The following observations were noted during necropsy of all animals: intestines, liver, lungs, kidney and spleen showed abnormalities that appeared dose related. The stomach and bladder showed sporadic abnormalities. Skin sloughing of the exposure area (1/10); skin oedema (7/8), skin redness (9/10) and skin hard/thickness (6/10) were also noted.

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 000 mg/kg bw

Quality of whole database:

The key study was the only study available and was assigned a Klimisch score of 2. The overall quality of the database is high.

Acute oral toxicity

There is one acute oral toxicity study available in rats.

In an acute oral toxicity study, 40 rats (10 per group) were given single oral doses of Trigustral at 1730, 2470, 3510 and 5000 mg/kg bw and observed after dosing.

The following treatment-related effects were noted: clincal signs (lethargy, diarrhea with piloerection, chromorhinorrhea and ptosis noted with higher doses); mortality (at the lowest dosage, 3/10 animals dies; at the highest dosage, only one animal survived during 4 days observation period); necropsy observations (intestines, liver, lungs, kidney and spleen showed abnormalities that appeared dose related. The stomach and bladder showed sporadic abnormalities). The oral LD 50 was3900 mg/kg bw (2900 - 5100 mg/kg bw; 95% CI)

Acute dermal toxicity

There is one acute dermal toxicity study available in rats.

In an acute dermal toxicity study, 10 rabbits were given single dermal dose of Trigustral at 5000 mg/kg bw and observed up to 14 days after dosing.

There were 2/10 deaths on day 1. Signs of toxicity noted in animal 1 from day 6 through day 14 were anorexia, lessened mobility due to severe edema & eschar of exposure site and ptosis; animal 1 was emaciated by day 14. The following observations were noted during necropsy of all animals: intestines, liver, lungs, kidney and spleen showed abnormalities that appeared dose related. The stomach and bladder showed sporadic abnormalities. Skin sloughing of the exposure area (1/10); skin oedema (7/8), skin redness (9/10) and skin hard/thickness (6/10) were also noted. The dermal LD 50 was >5000 mg/kg bw.

Based on the available information in the dossier, the substance Trigustral (EC No. 943-728-2) does not need to classified for acute toxiciy for specific target organ toxicity - single exposure when the criteria outlined in Annex I of 1272/2008/EC are applied.